Glycolyl derivatives of 1, 12-dimethylpolyhydrophenanthrene-1-carboxylic acid esters



United States Patent GLYCOLYL DERIVATIVES OF LIZ-DHWETHYL- POLYHYDROPHENANTHRENE -1- CARBOXYLIC ACID ESTERS George M. Picha, Skokie, 111., assignor, by mesne assignments, to G. D. Searle & 'Co., Skokie, 111., a corporation of Delaware N0 Drawing. Application November 23, 1953, Serial No. 393,958

Claims. (Cl. 260-103) The present invention is concerned with derivatives .of resin acids with partially saturated phenanthrene nuclei and, more particularly, with those containing an acyloxyacetyl side chain. The application is a continuationin-part of my copending application Serial No. 257,977, filed November '23, 1951, now abandoned.

'In the steroid series it has been found that such an acyloxyacetyl substituent, and especially an acetoxyacetyl substituent,, is present in, and inrpart responsiblerfor, the valuable therapeutic activity of the adrenal cortico'id hormones, such as desoxycorticosterone, cortisone and dihydrocortisone. I have now found that the introduction of such a side chain into a resin acid nucleus can produce valuable compounds for use in clinical medicine.

The resin acids and their lower alkyl esters which are suitable for the objects of this invention are those belonging to the phenanthrene series, which includes the various pimaric acids, dehydroabieticacid-and neoabietic acid, but excludes such compounds as ,agathic acid. The phenanthroid resin acids all have a common nuclear skeleton except only for a difference in unsaturation and in substitution in the 6- and 7+positions. The common features reveal a 1,12-dimethylpolyhydrophenanthrene-1- carboxylic acid of the type.

Zeiss in his review on resin acids published in Chemical Reviews, vol. 42, pages 163 et seq., 1948, shows that there is still some uncertainty as 'to the location of the double bonds in some of the acids. 'It is certain, however, that ring C in all unmodified resin acids contains at least one unsaturated carbon to carbon linkage.

My invention consists in the introduction of a group into ring C, R being a hydrogen or lower acyl radical. Such an acyl radical may be an acetyl, propionyl, butyryl, valeroyl, caproyl, benzoyl, toluoyl, benzenesulfonyl, toluenesulfonyl and like radicals.

The introduction of the acyloxyacetyl side chain into 2,767,1t52 Patented Oct. 16, 1956 the '7-position can be accomplished by a number of methods. One of the convenient starting materials is the methyl O-rnethyl-7-acetylpodccarpate of Campbell and Todd, described in Journal Am. Chem. Soc., vol. 62, page 1292, 1940, which has the structural formula:

on, 00 0 CH;

C O CH2 The 6-methoxy radical can be demethylated by conventional methods from the methyl O-methyl-7-acetylpodocal-pate, and the resulting 6-hydroxy compound can be converted to the 7-acyloxyacetyl derivativeby Way .of the .bromoketone.

In the case of the 7-substituted 1,12-dimethyl- 1,2,3,4,9,10,11,12-octahydrophenanthrene 1 carboxylic acid derivatives the group in the 7-position .is in most instances far more reactive than the sterically :hindered .group in'the l-position, which allows preferential treatment of groups in the 7-position.

Methyl O-methyl-7acetylpodocarpate can also be used as a starting material in an alternative-procedure. Subjected to the haloform reaction it forms'the :1-methy1 ester of the 7-carboxy derivative, i.e. the 1,12-dimethyl- 6 methoxy l,2,3,4-,9,l0,11,12-octahydrophenanthrene- 1,7-dicarboxylic acid. The 7-carboxy group, on treatment with a halogenating agent such as thionyl chloride, yields the carbonyl chloride which is made to react with diazomethane to form the diazoketone. The latter, on treatment with hydrogen bromide or with an acid such as glacial acetic acid, forms the bromoacetyl and acyloxyacetyl compounds respectively. The hydroxyacetyl derivative is obtained from the diazoltetone by hydrolysis with sulfuric acid.

Another useful source for the acyloxyacetyl radicals in the 7-position are the vinyl radicals of the d-pimaric and 7-iso-d-pimaric acids. The resulting products are of particular interest because they contain at the7-position a lower alkyl group in the cis-or trans-position in addition to the acyloxyacetyl radical. The pimar'ic acid l- 3 is oxidized with potassium permanganate to form the glycol of the structural formula CH3 COOH The carboxyl group in position 1 is esterified toform a lower alkyl ester, and the latter is oxidized with chromic acid to form the l-monoalkyl ester of the 1,7,12-trimethyl CH; C O OAlkyl The configuration of the CH3 and the CO-CHz-O-Acyl radical at the 7-position depends on whether the d-pimaric or the 7-iso-d-pimaric acid is employed. It may be most economical to employ the unseparated mixture as obtained from the resin,

It is also possible to introduce the acyloxy-acetyl radical into the ring C at positions "other than the 7-position. Acetylati-on of the methyl ester of dehydroabietic acid yields a mixture of acetyl derivatives (Cf. Fieser and Campbell, Journal Am. Chem. Soc., vol. 60, page 2635, 1938). The 6-position, being most reactive, is attacked most vigorously. The remaining acetyl derivatives consist primarily of the 8-acetyl compound with only a small quantity of the S-acetyl compound being formed. Trans- 0 7 formation of the acetyl radical by way of the bromoacetyl derivative yields the acyloxyacetyl derivative in the manner indicated hereinabove.

The compounds which constitut this invention are valuable as intermediates in organic synthesis, They are also of special value in clinical medicine. They have estrogenic, hypotensive and adrenocorticoid properties.

My invention will appear more fully from the following examples. It will be understood, however, that these V examples are set forth by Way of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details contained therein.- It

will be apparent to those skilled in the art that many modifications in materials and methods can. be made,

without departing from the scope of the invention. In each of these examples temperatures are given uncorrected in degrees centigrade C.) and quantities of materials in parts by weight.

Example I A mixture of 40 parts of methyl O-methyl-7-acetylpodocarpate with 285 parts of absolute ether and a trace amount of aluminum chloride is treated over a period of 15 minutes by the dropwise addition of 18 parts of bromine. Constant shaking is employed to insure a smooth reaction, The mixture is then diluted with 1000 parts of water, and the other is evaporated by gentle CH3 000cm l OCH;

Example 2 A solution is prepared from 5 parts of sodium acetate,

50 parts of Water, and sufficient acetic acid to make the solution neutral or barely acidic. 15 parts of the methyl Omethyl-7-bromoacetylpodocarpate and 315 parts of ethanol are added, and the entire mixture is heated under reflux for two hours. The solution is then concentrated to about 200 parts, at which point a yellow oil begins to separate. The mixture is diluted with about 1000 parts of water, and the gummy product is washed several times by decantation and then recrystallized from 95% ethanol. There are obtained dense, yellow-white crystals of the acetoxyketone, which melt at 127-128 C. A mixture with the bromoketone of melting point l52-l54 C. melts at 108-125 C. A mixture with slightly impure methyl O-methyl-7-acetylpodocarpate of melting point 109-110 C. melts at 9498 C. The methyl ester of O methyl-7-acetoxyacetylpodocarpic acid has the structural formula CH OOOCHa' COCHZOCOCHB Example 3 25 parts of methyl O-methyl-7-acetylpodocarpate are dissolved in 1000 parts of dioxane, and 300 parts of 10% sodium hydroxide are added. ThisI mixture is warmed to about 5060 C., and treated by the dropwise addition of a 221:8 solution of potassium iodide, iodine and Water until a persistent dark color results, indicating th pres- The dark color is removed by the addition of more sodium hydroxide, and the mixture is diluted to about 8000 parts with water. When the precipitation of iodoform is complete, it is removed by filtration, and 'the filtrate is acidified with dilute hydrochloric acid, The solid product is collected, washed with water, and recrystallized from ethyl acetate to give almost white crystals of methyl O-methyl-7- carboxypodocarpate which melt at about 164 C. and are readily soluble in dilute alkali. It will be apparent that a hypobromite or a hypochlorite may be substituted with qualitatively equivalent results for the hypoiodite which is the effective reagent in this transformation. The product has the structural formula H30 OOCH! COOH Because the ester grouping present in the starting material is derived from a sterically-hindered carboxyl group, no significant amount of hydrolysis of this ester occurs during the haloform reaction.

Example 4 Example 5 A solution of 200 parts of methyl O-methyl-Lacetylpodocarpate, 850 parts of glacial acetic acid, and 890 parts of 48% hydrobromic acid is heated under reflux for aperiod of from one to two hours. During the period of reflux, an insoluble oil separated from the solution. The mixture is cooled and poured, while stirring, into about 12,000 parts of water, and the product is collected on a filter and washed thoroughly with aqueous potassium bicarbonate and water. By three recrystallizations from ethanol there is obtained the almost white, crystalline methyl 7-acetylpodocarpate which melts at about 15l152 C. Although this compound has a free phenol grou it is almost insoluble in dilute sodium hydroxide. It has the structural formula H30 0 O O CHa QOCH:

Example 6 Treatment of the O-methyl-7-carboxypodocarpic acid of Example 4 by the demethylation procedure of Example 5 yields the 7 -carboxypodocarpic acid. Similar treatment of the methyl ester obtained in Example 3 yields the white, crystalline methyl ester of 7-carboxypodocarpic acid which has the structural formula H30 00 0 on,

Example 7 In a reaction vessel equipped with a drying tube, a mixture of parts of methyl O-methyl-7-carboxypodocarpate of Example 3, 500 parts of dry benzene, 300 parts of thionyl chloride, and a trace of pyridine is re,- fluxed for two hours, after which the mixture is distilled to dryness under vacuum. The residual acid chloride is purified for use in the next reaction by repeated trituration with 1:1 benzene-petroleum ether and removal of the solvent by vacuum distillation until the product is virtually free of acidic fumes. The product has the structural formula 11 C COOCHs C 0 Cl CH2 l O CH;

Example 8 The acid chloride prepared from 80 parts of methyl O-methyl-7-carboxypodocarpate is dissolved in 1000 parts of a 1:1 mixture of absolute ether and dry benzene, and this solution is added gradually to a five molar excess of diazomethane in ether solution, maintained at about 0-5 C. in an ice bath and protected from moisture by a drying tube. After addition of the acid chloride is complete, the reaction mixture is allowed to warm slowly to room temperature and then allowed to stand for 5 hours. A slight amount of residue is then removed by filtration and the filtrate is concentrated in a vacuum to a very small volume. The crude diazoketone which separates is washed with petroleum ether. It has the structural formula H10 00 O CH:

CO CHN2 CH3 l OCHs Example 9 parts of the crude diazoketone of Example 8 are dissolved in 2000 parts of dry ether, and this solution is chilled to about 0-5 C. in a flask equipped with a drying tube. The reaction mixture is treated by the dropwise addition of a solution of hydrogen bromide gas in dry ether, until the evolution of nitrogen from the mixture appears complete. The mixture is then treated with 5000 parts of water, and warmed gently until the ether is completely evaporated, leaving an aqueous suspension of the gummy bromoketone. When the gum Washed r'epeatedly by decantation and recrystallized several times from ethanol, there are obtained alr n ost white, cottony crystals of methyl O-methyl-7-bromoacetylpodocarpate, identical with the product of Example 1.

Example 1 A mixture of 50 parts of the diazoketone of Example 8 and 1000 parts of glacial acetic acid (in the absence of any metallic catalyst) is heated on a steam bath until the evolution of nitrogen gas from the mixture appears complete. The reaction mixture is then concentrated under vacuum to about b of its original volume, and diluted with 1000 parts-of water. The gummy precipitate is washed by decantation and purified by repeated recrystallization from 95% ethanol to give pale yellow crystals of the methyl ester of the 6-methyl ether of 7-acetoxyacetylpodocarpic acid, identical with the product of Example 2.

' Example 11 A solution of 20 parts of the diazoketone of Example '8 in 500 parts of dioxane (in the absence of any metallic catalyst) is acidified by the addition of dilute sulfuric acid, and allowed to stand at room temperature until the evolution of nitrogen gas appears complete. The mixture is then diluted with 3000 parts of Water and extracted with 3 portions of ether. The combined ether extracts are washed with dilute potassium carbonate and several portions of water, and then dried over anhydrous calcium sulfate and filtered. When the filtrate is evaporated to dryness, there is deposited the crude l-methyl ester of 1,12-dimethyl-6-methoxy 7 hydroxyacetyl- 1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid. 7

HsC COOCH;

COCHzOH OCHa' Example 12 A solution of 100 parts of the methyl ester of .dehydroabietic acid and 27 parts of acetyl chloride in 1000 parts of nitrobenzene is stirred at,0 C. and treated with 88 parts of aluminum chloride (cf. Fieser and Campbell, Journal Am. Chem.'Soc., vol. 60, page 2635, 1938). Stirring is continued until allof the material has entered into solution and the mixture is permitted to stand for 36 hours at 0 C., poured on ice and 240 parts of concentrated hydrochloric acid and steam distilled. The residue is taken up in ether and the ether solution washed with aqueous potassium bicarbonate, dried over calcium sulfate and decolorized with charcoal. Upon evaporation a mixture of the -,'6-, and 8-acetyl derivatives of the methyl ester of dehydroabietic acid is obtained with the 6-isomer predominating and the 5isomer being present in the smallest quantity.

Example 13 1 l A solutionof 100 parts of the mixture of the isomers 'obtained in Example 12 in 730 parts of absolute ether is treated with a trace amountof aluminum chloride and then inthe co urse of 15 minutes with 46 parts of bromine with constant shaking. The mixture is treated with 2000 parts of- Water and the ether removed in vacuum. A slightly gummy precipitate is formed which is collected on a filten'wash'ed with water, and recrystallized from ethanol. The yellowish crystals consist principally of the methyl ester' of 6-br0moacetyldehydroabictic acid which has the structural formula shown, below.

CO-GHzBr Example 14 To a solution of 10 parts of sodium acetate in 100 parts of water, suflicient acetic acid is added to lower the pH just below 7.0. parts of'the product of Example 13 and 640 parts of 95 ethanol are added and the mixture refluxed for 2 hours. The solution is concentrated until an oil begins to separate and then diluted with 1000 parts of water. The resinous product is washed repeatedly with water and. then recrystallized from 95% ethanol. The yellowish needles consist primarily of the 6-acetoxyacetyl derivative of the methyl ester of dehydroabietic acid and have the structural formula CH3 OOOCHa CH3 N p p 7 C0CH20C OCVH| Infrared maxima are observed at 5.7, 5.8, 6.0, 7.3 and 7.4 microns.

i Example 15 To a solution of 15 parts of sodium propionate in 100 parts of water, suflicient propionic acid is added to lower the pH just below 7.0. Then 30 parts of the product of Example 13 and 650 parts of ethanol are added and the mixture heated under reflux for 3 hours; The solution is concentrated in vacuum and the residue treated with 2000 parts of water. The 6-propionoxyacetyl'derivative of the methyl ester of dehydroabietic acid is thus obtained as a yellowish resin. The predominating ingredient has the structural formula H O COOCH;

Infrared maxima are observed at 5.7, 5.8, 6.0 and 7.9 microns. I a

' Example 16 parts of a mixture of d-pimaric acid and iso-7- d-pimaric acid, melting at l80 C., is dissolved in 3600 parts of 0.1 N potassium hydroxide with heating, and the solution poured into 50,000 parts of Warm water. After cooling a solution of 76, parts of potassium permanganate in 5000 parts of water is added slowly with stirring over a period of 10 hours while the temperature is maintained at 10 C. After decolorization is complete the manganese dioxide is filtered off and the solution evaporated on a water bath to about 8000 parts. Any additional manganese dioxide that forms is filteredofl.

The reaction product can be fractionated by the method of Ruzicka and Balas (Annalen d. Chemie, vol. 460, pages 202 et seq.; 1928). For the purposes of the subsequent experiments it is preferable to use the relatively crude mixture of the cisand transforms of the 1,7,12- trimethyl 7 (m,B-dihydroxyethyl)-1,2,3,4,5,6,7,9,10,11, 12,13-dodecahydrophenanthrene-l-carboxylic acids and esterify them to the corresponding ethyl esters.

325 parts of this ester mixture is suspended in 2000 parts of glacial acetic acid and digested at 55 C. with a solution of 120 parts of chromium trioxide in 2000 parts of glacial acetic acid and 200 parts of water for /2 hour. The mixture of the ethyl esters of the 7-cis and 7-trans forms of the 1,7,12-trimethyl-1,2,3,4,5,6,7,9,10,l1,12,13- dodecahydrophenanthrene-l,7-dicarboxylic acid is precipitated by vacuum distillation of the acetic acid and dilution with water. The precipitate is dissolved in an excess of 5% sodium hydroxide with slight warming, filtered and the filtrate is rendered acidic by addition of acetic acid. The precipitate is then recrystallized from methanol to yield a yellowish mixture of the ethyl esters of the 7-cis and 7-trans forms of 1,7,12-trimethyl-1,2,3,4,5,6,7,- 9,10,1 1,12,13 -dodecahydrophenanthrene-l ,7-dicarboxylic acid.

Example 17 100 parts of the mixture of the ethyl esters of the 7-cis and 7-trans forms of 1,7,12-trimethyl-1,2,3,4,5,6,7,9,10,- l1,12,l3-dodecahydrophenanthrene-1,7-dicarboxylic acid, 650 parts of anhydrous benzene and 375 parts of thionyl chloride is heated under a reflux condenser in the presence of a trace of pyridine for 3 hours, after which the mixture is distilled to dryness under vacuum. The residual acid chloride is purified for the subsequent reaction by repeated trituration with a mixture of equal volumes of benzene and petroleum ether and removal of the solvent until the product is free of acidic fumes. The product has the structural formula CH3 oooolm VCO Cl CH3 CH3 Example 18 The mixture of the cisand transforms of the acid chloride of Example 17 is dissolved in a mixture of 600 parts of absolute ether and 600 parts of dry benzene and the resulting solution is added in small portions to a 5 molar excess of diazomethane in ether solution while the temperature is maintained at 0 C. and all moisture is excluded. Upon completion of the addition the temperature is permitted to rise gradually to 20 C. and the mixture kept at that temperature for hours, after which it is filtered and the filtrate is concentrated in vacuum. The residue is washed with petroleum ether. The diazoketones have the structural formula OOCHN;

CH3 CH3 Example 19 A mixture of 100 parts of the diazoketones of Example 18' and 2000 parts of glacial acetic acid is heated on a steam bath until all evolution of nitrogen has ceased. The reaction product is concentrated in vacuum to about ,4 of its original volume and then dilutedwith 1000 parts of water. The resinous precipitate is washed repeatedly with water and upon repeated recrystallization from ethanol yellowish white crystals of the mixture of the ethyl esters of the 7-cis and 7-trans forms of 1,7,12-trimethyl-7-acetoxyacetyl-1,2,3,4,5,6,7,9,10,11,12,13 dode cahydrophenanthrene-l-carboxylic acid are obtained which have the structural formula Infrared maxima are observed at 5.8, 7.25, 8.0 and 9.5 microns.

Example 20 A solution of 10 parts of the diazoketones of Example 18 in 300 parts of dioxane is acidified by the addition of dilute sulfuric acid and allowed to stand at 30 C. until no more evolution of nitrogen gas is noticeable. After addition of 2000 parts of water the mixture is extracted repeatedly with ether and the ether extracts are combined, washed with dilute potassium carbonate solution, dried over anhydrous calcium sulfate, stirred with decolorizing charcoal, filtered and evaporated. The residue contains the 7-cis and 7-trans isomers of the ethyl ester of the 1,7,12-trimethy1-7-hydroxyacetyl-1,2,3,4,5,6,7,9,l0,11,12,- 13-dodecahydrophenanthrene-l-carboxylic acid. It has the structural formula OH: 000C2 3 I claim:

1. A lower alkyl ester of a 1,12-dimethylpolyhydrophenanthrene-l-carboxylic acid which is'unsaturated in the ring formed by carbon atoms 5,6,7,8,14 and 13, which is substituted in the said ring by a member of the class consisting of 6-(lower) alkoxy, 6-hydroxy, 7-methyl and 7-isopropyl radicals and contains attached to one of the carbons 6 and 7 a radical of the structural formula wherein R is a member of the class consisting of hydrogen and (lower alkyl) -CO radicals.

2. A lower alkyl ester of a 1,12-dimethyl-6-(lower)- alkoxy 7 (lower)alkanoyloxyacetyl-l,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid.

3. A lower alkyl ester of 1,12-dimethyl-6-methoxy 7 acetoxyacetyl 1,2,3,4,9,10,11,12 octahydrd phenanthrene-l-carboxylic acid.

4. The methyl ester of 1,12-dimethyl-6-methoxy-7-acetoxyacetyl-1,2,3,4,9,10,-1 1,12 ocetahydrophenanthrene-lcarboxylic acid.

5. A lower alkyl ester of a 1,7,12-trimethyl-7-(lower) alkanoyloxyacetyl-1,2,3,4,5,6,7,9,10,11,12,13 dodecahy- 2,767,162 I1 '12 drophenanthrene-l-carboxylic acid of the' structural 8. A lower alkyl ester of a 1,12-dimethy1-6- (lower)a1- formula r kanoyloxyacetyl-7-isopropyl-1,2,3,4,9,10,11,12-octahydro- H3 C0O ('1ower)mky1 phena n threne-l-carboxylicr acid of the structural formula CH; CO0(l0wer)A1kyl co-cnr-o-o O(1ower)alkyl Ha CH3 V V V V 6. A lower alkyl ester of the 1,7,12-trimethy1-7-acetoxy- H5 H acetyl 1,2,3,4,5,6,7,9,10,11,12,13 dodeeahydrophenan C O O 9 are Garb oxyli c acid. V 9 A lower alkyl ester of 1,12-d1methyl-6-acetoxyacetyl- 7. A lower alkyl ester of a 1,12-dimethy1-7-isopropyl- 7 9 i LLB/1,9,10,11,12 octahydrophenanthrene 1 carboxylic carboxyhc acid substituted in ring C by a lower alkanoyloxyacetyl The met yl ester pf 11Z'dlmethylGTaeetoxyaCetyl' radical of the structural formula 7-1s0propy1- 1 ,2,3,4,9,10,11,l2-octahydrophenanthrene-1 V carboxylic acid. CH3 C00(lower)A1kyl q No references cited. 

1. A LOWER ALKYL ESTER OF A 1,12-DIMETHYLPOLYHYDROPHENANTHRENE-1-CARABOXYLIC ACID WHICH IS UNSATURATED IN THE RING FORMED BY CARBON ATOMS 5,6,8,14 AND 13, WHICH IS SUBSTITUTED IN THE SAID RING BY A MEMBER OF THE CLASS CONSISTING OF 6-(LOWER) ALKOXY, 6-HYDROXY-7-METHYL AND 7-ISOPROPYL RADICALS AND CONTAINS ATTACHED TO ONE OF AND CARBONS 6 AND 7 A RADICAL OF THE STRUCTURE FORMULA 